Effect of weight loss on intermuscular adipose tissue (IMAT) signaling

肌间脂肪组织(IMAT)在骨骼肌中有大理石花纹，似乎在 肥胖导致患2型糖尿病的风险。目前尚不清楚IMAT是如何促进肌肉胰岛素减少的 敏感度。迫切需要了解IMAT如何导致肥胖引发的糖尿病风险， 以及如何干预以将IMAT引起的肌肉代谢功能障碍降至最低。这个项目的总体目标是 项目是确定减肥对IMAT分泌纤维连接蛋白和炎性细胞因子的影响 和二十烷类化合物。我们的中心假设是IMAT分泌的纤维连接蛋白促进肌肉胰岛素 抵抗，而炎性细胞因子和二十烷类化合物的分泌会导致肌肉炎症，两者都 其中一些会因体重减轻而减少。这项拟议研究的基本原理是，澄清 体重减轻改变IMAT分泌组的程度将通知修改IMAT的干预措施的发展 并改善肥胖者的肌肉胰岛素敏感性。我们提出了两个具体目标：具体目标1。 评价减肥对IMAT分泌纤维连接蛋白的影响及纤维连接蛋白在IMAT中的作用 分泌组能在体外降低胰岛素敏感性。初步数据告诉我们的工作假设是IMAT 分泌纤维连接蛋白，降低肌肉对胰岛素的敏感度，并在人类减肥后减弱。在……里面 体外实验将测量IMAT纤维连接蛋白分泌解释IMAT诱导的肌肉的程度 胰岛素抵抗。我们将对肥胖患者进行为期12周的减肥干预前后的研究。 IMAT将使用超声引导的IMAT活检技术进行采样，胰岛素敏感性测量使用 胰岛素钳夹，MRI测量IMAT含量。具体目标2--确定权重的影响 促炎症细胞因子和二十烷类化合物的IMAT分泌丧失，以及引起炎症和 降低体外胰岛素敏感性。我们再次根据初步数据推测，IMAT分泌组 肥胖者减肥后炎症较轻，促进肌肉的能力降低 炎症和胰岛素抵抗。IMAT分泌组的肌肉炎症反应和胰岛素敏感性 将在体外比较减肥前后的暴露情况。这项拟议的研究具有创新性，因为 通过测试特定的IMAT分泌的旁分泌，它代表了对现状的新的实质性偏离 信号，而不是临床与IMAT内容的关联。这些贡献将是重大的，因为确定了 第一个IMAT旁分泌信号冲击肌肉，通过减肥揭示IMAT的可塑性， 提供概念证据，证明IMAT是对抗肌肉代谢功能障碍的治疗靶点。

Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the obesity-induced risk of type 2 diabetes. What is not known is how IMAT promotes decreased muscle insulin sensitivity. There is a critical need to understand how IMAT contributes to the risk of obesity-induced diabetes, and how to intervene to minimize IMAT-induced muscle metabolic dysfunction. The overall objective for this project is to determine the impact of weight loss on IMAT secretion of fibronectin and inflammatory cytokines and eicosanoids. Our central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin resistance, and IMAT secretion of inflammatory cytokines and eicosanoids causes muscle inflammation, both of which are diminished by weight loss. The rationale that underlies the proposed research is that clarifying the extent to which weight loss alters the IMAT secretome will inform development of interventions to modify IMAT and improve muscle insulin sensitivity in obese individuals. We propose two specific aims: Specific Aim 1. Evaluate the impact of weight loss on IMAT secretion of fibronectin and the role of fibronectin in the IMAT secretome to decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT secretes fibronectin that decreases muscle insulin sensitivity and is attenuated after weight loss in humans. In vitro experiments will measure the extent to which IMAT fibronectin secretion explains IMAT-induced muscle insulin resistance. We will study individuals with obesity before and after a 12-week weight loss intervention. IMAT will be sampled using an ultrasound guided IMAT biopsy technique, insulin sensitivity measured using insulin clamps, and IMAT content measured using MRI. Specific Aim 2 – Determine the influence of weight loss on IMAT secretion of pro-inflammatory cytokines and eicosanoids and potency to cause inflammation and decrease insulin sensitivity in vitro. We hypothesize, again based on preliminary data that the IMAT secretome is less inflammatory after weight loss in obese individuals, with decreased potency to promote muscle inflammation and insulin resistance. Muscle inflammatory response and insulin sensitivity with IMAT secretome exposure will be compared before and after weight loss in vitro. The proposed research is innovative because it represents a new and substantive departure from the status quo by testing specific IMAT secreted paracrine signals rather than clinical associations with IMAT content. These contributions will be significant by identifying the first IMAT paracrine signals that impact muscle and revealing the plasticity of IMAT through weight loss, providing proof of concept that IMAT is a therapeutic target to combat muscle metabolic dysfunction.